EP1608649A2

EP1608649A2 - Method for the enantioselective preparation of sulphoxide derivatives

Info

Publication number: EP1608649A2
Application number: EP04742382A
Authority: EP
Inventors: Avraham Cohen; Suzy Charbit; François SCHUTZE; Frédéric MARTINET
Original assignee: Sidem Pharma SA
Current assignee: Sidem Pharma SA
Priority date: 2003-03-28
Filing date: 2004-03-26
Publication date: 2005-12-28
Also published as: WO2004087702A3; JP2006523201A; US20060281782A1; CA2520157A1; WO2004087702A2; KR20060002878A

Abstract

The invention relates to a method for the enantioselective preparation of substituted sulphoxide derivatives. The method comprises carrying out an enantioselective oxidation of a sulphide of general formula (I): A - CH2 - S - B (I), where A = a variously-substituted pyridyl nucleus and B = a heterocyclic group with a benzimidazole or imidazopyridyl nucleus, by means of an oxidising agent in the presence of a catalyst based on tungsten or vanadium and a chiral ligand, followed, where necessary, by salt formation with a base to give the sulphoxide: A - CH2 - SO - B (Ia). The above is of application to the enantioselective preparation of compounds such as the enantiomers of tenatoprazole and other comparable sulphoxides.

Description

PROCESS FOR THE ENANTIOSELECTIVE PREPARATION OF SULFOXIDE DERIVATIVES.

The present invention relates to a process for the enantioselective preparation of substituted sulfoxide derivatives, and more particularly to a process for the enantioselective preparation of compounds such as the enantiomers of tenatoprazole and other comparable sulfoxides.

Various sulfoxide derivatives are known, and in particular pyridinyl-methyl-sulfinyl benzimidazoles, useful in therapeutics as medicaments having inhibitory properties of the proton pump, that is to say medicaments which inhibit the secretion of gastric acid and are useful for the treatment of gastric and duodenal ulcers. The first known derivative of the proton pump inhibitor series is omeprazole, or 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] suifinyl] -lH- Benzimidazole described in patent EP 001,529, which has inhibitory properties for gastric acid secretion, and is widely used as an anti-ulcer in human therapy. Other benzimidazole derivatives with similar structure are known by their generic names, for example rabeprazole, pantoprazole, lansoprazole, which all have a structural analogy, and belong to the group of pyridinyl-methyl-sulfinyl-benzimidazoles.

Tenatoprazole, i.e. 5-methoxy-2- [[((4-metho-xy-3, 5-dimethyl-2-pyridyl) methyl] suifinyl] imidazo [, 5-b] pyridine , is described in patent EP 254,588. It is also one of the drugs considered to be proton pump inhibitors, and it can also be used in the treatment of gastroesophageal reflux, digestive bleeding and dyspepsia. All these compounds are sulfoxides having an asymmetry at the level of the sulfur atom and can therefore be in the form of a racemic mixture of two enantiomers. It may be useful to separate them selectively under the shape of one or the other of the two enantiomers having the configurations R and S, or (+) or (-), respectively, the specific properties of which may be significantly different. Various processes have been described in the scientific literature for the selective or preponderant preparation of one or the other of the enantiomers of these sulfoxides, in particular omeprazole and its enantiomer of configuration S, esomeprazole, as well as its salts such than sodium or magnesium salt. Thus, patent EP 652,872 describes a process for preparing the magnesium salt of the (-) enantiomer of omeprazole via the ester comprising a chiral acyloxymethyl group, separation of the diastereoisomers and solvolysis in an alkaline solution. US Patent 5,776,765 describes a process using the stereoselective bioreduction of the racemic mixture of the sulfoxide to the corresponding sulfide, using a microorganism comprising a DMSO reductase, making it possible to obtain a mixture highly enriched in (-) enantiomer relative to the (+) enantiomer. US Patent 5,948,789 relates to the enantioselective preparation of sulfoxides, and more particularly of the (-) enantiomer of omeprazole or of its sodium salts, by oxidation of the corresponding sulfide by a hydroperoxide in the presence of a titanium complex and a chiral ligand. The process described in this patent makes it possible to obtain a mixture enriched in one or the other of the enantiomers (-) and (+), according to the ligand used.

The work carried out by the Applicant has made it possible to show that it is possible to obtain enantioselective manner enantiomers of sulfoxide derivatives, and in particular tenatoprazole, under good conditions of yield and purity, by enantioselective oxidation of the corresponding sulfide in the presence a specific catalyst based on tungsten or vanadium.

The subject of the present invention is therefore a process for the enantioselective preparation of sulfoxide derivatives having an asymmetry at the level of the sulfur atom, providing either of the enantiomers with good purity and satisfactory yield.

A very particular subject of the invention is a preparation process which provides, substantially enantio-selectively, the (-) enantiomer and the (+) enantiomer of tenatoprazole. The term "substantially enantioselective" as used herein means that the desired enantiomer is obtained selectively or in a predominant amount over the other enantiomer. In accordance with the process of the invention, an enantioselective oxidation of a sulfide of general formula (I) below is carried out

A - CH ₂ - S - B (I) in which A is a variously substituted pyridyl ring and B a heterocyclic residue comprising a benzimidazole or imidazo-pyridyl ring, by means of an oxidizing agent in the presence of a catalyst based on tungsten or vanadium and a chiral ligand, followed where appropriate by base salification. In the general formula (I) above, A preferably represents a pyridyl group or a pyridyl group carrying one or more substituents chosen from linear or branched alkyl groups of 1 to 6 carbon atoms, linear or branched alkoxy of 1 to 6 carbon atoms, methyl or ethyl substituted by one or more halogen, amino, alkylamino or dialkylamino atoms where the alkyl part, linear or branched, contains 1 to 5 carbon atoms; B represents a heterocycle chosen from the benzimidazole or imidazo- groups

[4, 5-b] -pyridyl, substituted where appropriate by one or more linear or branched alkyl groups of 1 to 6 carbon atoms, linear or branched alkoxy of 1 to 6 carbon atoms, and preferably substituted on one or several carbons by a methyl, ethyl, methoxy or trihalogenomethyl group. In the general formula (I) above, A is preferably a 2-pyridyl group substituted by one or more methyl, ethyl, methoxy or trifluoromethyl groups, and more particularly a 4-methoxy-3, 5-dimethyl-2-pyridyl group. B is preferably a 5-methoxy-1H-benzimidazolyl or 5-methoxy-imidazo- [4,5-b] -pyridyl group. The sulfide of formula (I) above is a known product which can be prepared by various methods described in the literature, and for example by the methods described in patents EP 254,588 and EP 103,553.

A sulfoxide of general formula A - CH ₂ - SO - B (la) in which A and B have the above definitions is thus obtained.

The oxidant used in the process of the invention is preferably a peroxide, for example hydrogen peroxide, or a hydroperoxide, for example 1 cumene or tert-butyl hydroperoxide. According to an advantageous embodiment, hydrogen peroxide at high concentration, for example greater than 30%, or hydrogen peroxide complexed by urea (UHP: urea hydrogen peroxide H ₂ NCONH ₂ .H ₂ 0 ₂ ) is used, ci- after also called "UHP". The catalyst based on tungsten or vanadium is an essential element of the process of the invention, which makes it possible to promote the reaction and to obtain the desired derivative with good yield. According to the invention, a catalyst is preferably used such as an oxo-vanadium complex (V), for example prepared from vanadium acetylacetonate VO (acac) ₂ / or also a tungsten derivative, for example example prepared from tungsten trioxide 0 ₃ . Such catalysts are commercially available. It is also possible to use a complex prepared from vanadium sulphate VOS0 ₄ . The choice of ligand constitutes another characteristic element of the invention because it is an inducer of chirality; it makes it possible to selectively orient the reaction towards the desired enantiomer.

In the context of the present invention, in the case of a vanadium-based catalyst, the ligand is preferably tridentate. The ligand can advantageously be represented by the following general formula (II):

RO-CRιR ₂ -CR ₃ R ₄ -NR ₅ R ₆ (II) where R is a hydrogen atom or a linear or branched alkyl group of 1 to 6 carbon atoms or an aryl or heteroaryl group;

Ri to R ₄ , identical or different, represent a linear or branched alkyl group of 1 to 6 carbon atoms which can optionally be interrupted by a heteroatom such as sulfur, nitrogen and oxygen and / or be substituted by a group amino; an aryl group; an arylalkyl group; an alkoxycarbonyl group; a heteroaryl group or a heterocycle; a heteroarylalkyl group or a heterocyclalkyl group, with the proviso that Ri is not identical to R ₂ and / or R ₃ is not identical to R ₄ , so that the ligand has one or two centers of d 'asymmetry; Ri and R ₂ can together represent a carbonyl function C = 0; Ri and R ₃ , or R ₂ and R ₄ , can together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system with 9 or 10 carbon atoms, one of the rings of which may be aromatic; Likewise, R ₄ and R ₅ can form, with the nitrogen atom, a 5 or 6-membered heterocycle; R ₅ and R _β , identical or different, represent a linear or branched alkyl group of 1 to 6 carbon atoms or a carbon ring comprising 5 or 6 members, or form a heterocycle with the nitrogen atom to which they are attached, or R ₅ and R ₆ together represent with nitrogen a double bond -N = CHAr where Ar is an aryl group which may contain from 1 to 3 substituents, preferably carrying a hydroxyl group.

Preferably, Ar is a 2 '-hydroxyphenyl group optionally substituted on the aryl group.

Preferably Ri and R ₃ , or R ₂ and R ₄ , represent a hydrogen atom, while R ₂ and R ₄ , or Ri and R ₃ , respectively, are, independently of each other, alkyl groups linear or branched from 1 to 6 carbon atoms, an aryl group or together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system with 9 or 10 carbon atoms one of the rings of which may be aromatic. In the context of the present invention:

an “aryl group” preferably means a mono- or polycyclic system having one or more aromatic rings among which mention may be made of the phenyl group, the naphthyl group, the tetrahydronaphthyl group, the indanyl group and the binaphthyl group. The aryl group may be substituted by 1 to 3 substituents chosen independently of one another from a hydroxyl group, a linear or branched alkyl group containing from 1 to 4 carbon atoms such as methyl, ethyl, propyl or preferably fcert-butyl, a nitro group, a (C _ι -C ₄ ) alkoxy group and a halogen atom, such as chlorine, bromine or iodine,

- an “arylalkyl group” preferably means an aryl group linked to an alkyl group comprising from 1 to 4 carbon atoms, - an “alkoxycarbonyl group” preferably means an alkoxy group comprising from 1 to 4 carbon atoms linked to a group carbonyl, such as the methoxycarbonyl group,

a "heteroaryl group" preferably means an aryl group comprising from 1 to 3 heteroatoms, such as nitrogen, sulfur or oxygen, and as such heteroaryl group mention may be made of pyridyl, pyrazinyl, pyridazinyl , quinolyl, isoquinolyl, etc,

- A "heterocycle" or "heterocyclic group" preferably means a 5 or 6-membered ring containing from 1 to 3 heteroatoms such as sulfur, nitrogen and oxygen. This definition also contains bicycles where a heterocyclic group as defined above is fused with a phenyl group, a cyclohexane group or another heterocycle. Mention may be made, among heterocyclic groups, of imidazolyl, indolyl, isoxazolyl, furyl, pyrazolyl, thienyl, etc. a “heteroarylalkyl” group preferably means a heteroaryl group linked to an alkyl group containing from 1 to 4 carbon atoms, preferably methyl,

a “heterocyclalkyl group” preferably means a heterocyclic group linked to an alkyl group comprising from 1 to 4 carbon atoms, preferably methyl, such as 4-imidazolylmethyl.

More particularly, the ligand of formula (II) can in particular be a derivative:

- an amino alcohol of formula (III)

in which Ri, R ₂ , R ₃ and R ₄ are as defined above. Among the amino alcohols of formula (III), mention may especially be made of - (£ - (+) -) or D-valinol (R- {-) -2-amino-3-methyl-1-butanol), R - tert-leucinol (R- {-) -2-amino-3, 3-dimethyl-1-butanol) S- tert-leucinol {S- (+) -2-amino-3, 3-dimethyl-1- butanol), and (1S, 2R) - {-) - or (12 ?, 23) - (+) -1- amino-2 -indanol,

- an amino ether of formula (IV)

in which R, Ri, R ₂ , R ₃ and R ₄ are as defined above. - an amino acid of formula (V)

in which R 'takes the definition of R ₃ or R ₄ as previously given. Among the amino acids of formula (V), mention may in particular be made of L-valine or D-valine, -phenylalanine or D-phenylalanine, L-methionine or D-methionine, L-histidine or D-histidine and L-lysine or D-lysine. an amino ester of formula (VI)

in which R 'takes the definition of R ₃ or R ₄ as previously given and R''takes the definition of R.

Preferably, in order to obtain particularly advantageous ligands, namely Schiff bases, these amino alcohol, amino ether, amino acid and amino ester are reacted respectively with formulas (III), (IV), (V ) and (VI) with an aldehyde of salicylic acid, of formula (VII)

in which R ₇ represents 1 to 2 substituents chosen independently of one another from a hydroxyl group, a linear or branched alkyl group comprising from 1 to 4 carbon atoms such as methyl, ethyl, propyl or preferably tert -butyl, a nitro group, a group (Cι-C ₄ ) alkoxy and a halogen atom, such as chlorine, bromine or iodine.

In the context of the present invention, very particularly preferred are the ligands of formula (II), derived from an amino alcohol of formula (III), for which R ₅ and R _s together represent with nitrogen a double bond - N = CHAr where Ar is an aryl group comprising from 1 to 3 substituents and at least one hydroxyl group, Ar preferably being a phenyl group, Ri and R ₃ , or R ₂ and R ₄ , represent a hydrogen atom, while that R ₂ and R ₄ , or R _x and R ₃ , respectively, are, independently of each other, linear or branched alkyl groups of 1 to 6 carbon atoms, preferably a group tert-butyl or together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system with 9 or 10 carbon atoms in which one of the rings can be aromatic, preferably 1 indanyl. According to the present invention, a ligand can advantageously be chosen according to the catalyst used, and for example in the case of tungsten, a ligand can be used according to the desired enantiomer:

- belonging to the family of quinine alkaloids such as quinine, quinidine, dihydroquinidine (DHQD) or dihydroquinine (DHQ),

- derived from quinine alkaloids such as 2,5-diphenyl-4,6-pyridinediyl hydroquinine diether (DHQ) ₂ -PYR or 2,5-diphenyl-4,6-pyridinediyl hydroquinidine diether (DHQD ) ₂ -PYR.

In the case of a vanadium-based catalyst, use is preferably made of a ligand represented by the formula (II) above comprising a substituent on nitrogen, and for example a Schiff base derived from a substituted salicylic aldehyde and a chiral amino alcohol.

Generally, use is preferably made, in the case of a vanadium catalyst taken in the form of vanadium acetylacetonate, of a ligand derived from an amino alcohol or an amino ether respectively of formula (III) or (IV) defined above. Conversely, in the case of a vanadium-based catalyst taken in the form of vanadium sulfate, a ligand derived from an amino acid or from an amino ester of formula (V) or (VI) as defined above. Thus in the case of a vanadium-based catalyst, preferably taken in the form of vanadium acetylacetonate, the ligands 2, 4-di-tert-butyl-6- [l-2? -Hydroxymethyl-2 -methyl- propylimino) -methyl] -phenol and its isomer 2,4-di-tert-butyl-6- [1S-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol which allow to selectively direct the reaction towards The desired enantiomer, are particularly preferred Thus, the use of 2,4-di-tert-butyl-6- [l-2? -Hydroxy-methyl-2-methyl-propylimino) -methyl] -phenol makes it possible to selectively orient the oxidation reaction of 5-methoxy-2- [[4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4, 5-b] pyridine, to selectively obtain S-tenatoprazole, as indicated below -after.

Likewise, still in the case of a vanadium-based catalyst, preferably taken in the form of vanadium acetylacetonate, the ligand (12 ?, 2S) - 1 - [2-hydroxy-3, 5-di-tert -butyl- benzylidene) -amino] -indan-2-ol, derived from amino-indanol as amino alcohol, is very particularly preferred. Thus, the use of this ligand makes it possible to selectively orient the oxidation reaction of 5-methoxy-2- [[[4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4, 5-b] pyridine, to selectively obtain S-tenatoprazole, as indicated below.

Under the operating conditions, the ligand, preferably tridentate, forms with the metal catalyst an asymmetric complex where the metal is oxidized by the oxidant. According to one embodiment of the process of the invention, the reaction can be carried out in a solvent, and preferably in a mixture of solvents, in a neutral or weakly basic medium, by choosing a specific solvent for sulfide and a specific solvent ligand, chosen from the group consisting of methanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetone, chloroform, DMF (dimethylformamide) or NMP (N-methylpyrrolidinone), or in mixture. The base used, where appropriate, can be a tertiary amine such as pyridine, di-isopropylethylamine or triethylamine.

According to a variant, the process can be carried out without adding a base, but it is preferable to avoid working in an acid medium which could lead to degradation of the final product. It is very particularly advantageous, according to the invention, to use the vanadium-based catalyst and the ligand in solution in acetonitrile, while the sulphide is in solution in a chlorinated solvent such as dichloromethane, NMP or acetone and to combine the two solutions, then to act 1 oxidant. The oxidation reaction is easily carried out cold or at room temperature. It may be more advantageous to carry out the reaction at a temperature between 0 and 10 ° C and preferably about 4 to 5 ° C to promote enantioselectivity. The process of the invention is particularly advantageous insofar as the oxidant and the catalyst are widely available commercially, inexpensive and easy to use. In addition, the catalyst can be used effectively in very small amounts. The yield obtained as an enantiomer is excellent, and, in addition, the catalyst and the ligand can generally be recycled under good conditions without loss of the enantiomeric excess.

The process of the present invention is very particularly advantageous in the case of the preparation of the enantiomers of tenatoprazole which can be represented by the following general formula:

Thus, for example, according to the method of the invention, it is advantageous to carry out an enantioselective oxidation of 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] - thio] imidazo [4, 5-b] pyridine by hydrogen peroxide in the presence of tungsten trioxide and (DHQD) ₂ ~ PYR / to obtain the (-) - 5-methoxy-2- [[((4-methoxy-3 , 5-dimethyl-2-pyridyl) methyl] sufinyl] imidazo [4, 5-b] pyridine. More particularly, it has been found that the oxidation of the above sulfide makes it possible to obtain the (-) enantiomer, of configuration S, under excellent conditions of purity and yield if a catalyst based on associated vanadium is used. to a ligand consisting of 2,4-di-tert-butyl-6- [1-2? - 2-hydroxymethyl-methyl-propylimino) -methyl] -phenol or (12 ?, 2 S) -1- [2-hydroxy-3, 5-di- ert-butyl-benzylidene) -amino] -indan- 2- ol in solution in acetonitrile, while the sulfide is in solution in dichloromethane, or respectively in acetone or NMP.

Conversely, the (+) isomer, of configuration 2?, Can also be obtained under excellent conditions of selectivity and yield by using as ligand 2,4-di-tert-butyl-6- [1S-hydroxymethyl- 2-methyl-propylimino) -methyl] -phenol, {18, 22?) -1- [2-hydroxy-3, 5-di-tert-butyl-benzylidene) -amino] -indan-2-ol.

The enantiomers (-) and (+) of tenatoprazole can be used in the form of salts, in particular of alkali or alkaline earth metal salt, and for example in the form of sodium, potassium, lithium, magnesium or calcium. These salts can be obtained from the (-) or (+) enantiomer of the previously isolated tenatoprazole, by salification reaction according to a usual method of the technique, for example by action of basic mineral reagents comprising alkaline or alkaline counter ions earthy.

Of course, the enantiomers (-) and (+) can be obtained in optically pure form simply from the racemic mixture, by any suitable separation method, and more particularly by a method of preparative column chromatography, for example by chiral chromatography . The enantiomers thus separated can be used for controls. By "optically pure form" is meant that

The (-) enantiomer is substantially free of the enantiomer

(+) or includes only traces of it, and vice versa. If appropriate, base salification is then carried out in an appropriate solvent, to form a salt, in particular an alkali or alkaline earth metal salt.

The principle of the chiral chromatography method is well known and is based on the difference in affinity between the (+) and (-) enantiomers and the chiral selector of the stationary phase. This method makes it possible to separate the enantiomers with a good yield.

The (-) enantiomer of tenatoprazole corresponds to (-) - 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] sufinyl] imidazo [4, 5- b] pyridine, or (-) -tenatoprazole. This shape can be determined by optical rotation measurements according to the usual techniques. Thus, the optical angle of rotation of (-) -tenatoprazole is levorotatory in dimethylformamide, and its melting point is 130 ° C (decomposition).

In the case of chiral separation of tenatoprazole, the racemic mixture used as starting material can be obtained by known methods, for example according to the method described in patent EP 254,588. Thus, it can be prepared by treating with an oxidizing agent, such as a perbenzoic acid, the corresponding sulfide originating from the condensation of a thiol and a pyridine, preferably in the presence of a base such as hydroxide. potassium in a suitable solvent, for example ethanol, hot. The enantiomers (-) and (+) of tenatoprazole, in the treatment of the pathologies indicated below, can be administered in the usual forms suitable for the chosen mode of administration, for example by oral or parenteral route, preferably by oral route or intravenous. It is possible, for example, to use formulations of tablets or capsules containing one or the other of the enantiomers (-) and (+) of tenatoprazole as active ingredient, or alternatively oral solutions or emulsions or solutions for parenteral administration containing a tenatoprazole salt with a usual pharmaceutically acceptable carrier. The enantiomer salt of tenatoprazole can be chosen, for example, from sodium, potassium, lithium, magnesium or calcium salts.

The (-) and (+) enantiomers of tenatoprazole obtained by the process of the present invention can be used in the manufacture of medicaments for the treatment of digestive pathologies, in particular those where an inhibition of acid secretion must be intense and prolonged, for the treatment of the symptoms and lesions of gastroesophageal reflux, digestive hemorrhages resistant to other inhibitors of the proton pump.

The dosage is determined by the practitioner depending on the patient's condition and the severity of the condition. It is generally between 10 and 120 mg, preferably between

20 and 80 mg, (-) or (+) enantiomer of tenatoprazole per day.

Examples of preparation of enantiomers are described below in order to illustrate the present invention without limiting its scope.

Example 1 Preparation of (3) - (-) -tenatoprazole

10 g of W0 ₃ , 73 g of (DHQD) ₂ -PYR, 3.5 L of THF and 330 g of 5-methoxy-2- [[4-methoxy- 3, 5 are introduced into a 5 L flask -dimethyl-2-pyridyl) methyl] thio] imidazo [4, 5-b] pyridine which is kept under stirring at a temperature between 4 and 5 ° C, and 120 ml of 30% hydrogen peroxide is added . The reaction medium is kept under stirring for 48 hours, then the catalyst is filtered and the filtrate is diluted in 10 L of dichloromethane at room temperature.

The organic phase is washed with water, then dried and concentrated under reduced pressure. 242 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 90% (yield 70%).

Recrystallization is carried out in the methanol / water or DMF / ethyl acetate mixture and the enantiomer is obtained with an enantiomeric excess greater than 99%. The enantiomeric excess is determined by high pressure liquid chromatography with a CHIRALPAK AS-H 20 μm column (250 x 4.6 mm) at 25 ° C, the eluent is acetonitrile (1 mL / min) and detection is performed by UV spectroscopy at 305 nm. The retention time of the {S) - (-) isomer is 7.7 min and that of the (2?) - (+) isomer is 5.2 min. T _F : 129-130 ° C

[α] ²⁰ _D : -186.6 (C 0.1, DMF) Elementary analysis:

UV spectrum (methanol-water): λ _max : 272 nm (ε = 6180), 315 nm (ε = 24877).

Infrared (KBr): 3006, 1581, 1436, 1364, 1262, 1026, 1040 and 823 cm ^"1. ¹ H NMR (DMSO d ₆ , reference: TMS) δ (ppm): 2.20 (s, 6H ), 3.70 (S, 3H), 3.91 (s, 3H), 4.69-4.85 (m, 2H), 6.80 (d, J 8, 5 Hz, 1H), 7, 99 (d, J 8.5 Hz, 1H), 8.16 (s, H), 13.92 (s, 1H).

¹³ C NMR (DMSO d _s , reference: TMS) δ (ppm): 13.2; 15.0; 56.6; 60.8; 62.6; 107.2; 129.5; 130.4; 131.9; 135.1; 150.5; 151.4; 156.9; 160.7; 163.0; 166.6.

Example 2 Preparation of (2?) - (+) -tenatoprazole The procedure is as in Example 1, replacing (DHQD) ₂ -PYR with (DHQ) ₂ -PYR, causing 120 ml of hydrogen peroxide to act on the same amount of 5-methoxy-2- [[((4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4, 5-b] pyridine as in Example 1 and using the same catalyst.

The desired (+) enantiomer is thus obtained with an enantiomeric excess greater than 99%, after recrystallization from the DMF / ethyl acetate mixture.

The rotary power, measured with a polarimeter, in dimethyl formamide is [α] ²⁰ _D = + 186 °.

The physical and spectroscopic constants of (2?) - (+) - tenatoprazole are identical to those of (S) - (-) -tenatoprazole, except for the specific rotary power: [α] ²⁰ _D : +185.9 ( c 0.1, DMF). Example 3

Preparation of {S) - (-) -omeprazole (esomeprazole) Using the operating conditions of Example 1, and using 5-methoxy-2- [[((4-methoxy-3, 5-dimethyl-2- pyridyl) methyl] thio] -1H-benzimidazole in place of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4, 5-b] pyridine, the desired product is obtained (esomeprazole) with an enantiomeric excess close to 90% (yield 72%). The product obtained complies with the analytical data available in the literature.

Example 4

Preparation of (S) - (-) -tenatoprazole 3 L of dichloromethane are introduced into a 5 L flask, then 360 g of 5-methoxy-2- [[4-methoxy-3, 5-dimethyl] -2 - pyridyl) methyl] thio] imidazo [4, 5-b] pyridine. The mixture is left stirring at room temperature for 30 min.

700 ml of acetonitrile, 5.22 g of 2,4-di-tert-butyl-6- [l-2? -Hydroxy-methyl-2-methyl-propylimino) are successively introduced into a 2 L flask. methyl] -phenol, then 2.90 g of vanadium acetylacetonate. The mixture is stirred at room temperature. After 30 min of stirring this solution is added to the previous one.

To this mixture, with stirring, 135 ml of 30% hydrogen peroxide are added for 20 h at room temperature. After separation of the aqueous phase, the organic phase is washed twice with water, then dried and concentrated under reduced pressure. 283 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 80% (yield 75%). Two successive recrystallizations are carried out in a methanol / water or DMF / ethyl acetate mixture and the enantiomer is obtained with an enantiomeric excess greater than 99%. T _F : 127.5 ° C [α] ²⁰ _D : -182 (c 0.1, DMF) Example 5

Preparation of (2?) - (+) -tenatoprazole The procedure is as in Example 4, replacing 2, 4-di-tert-butyl-6- [l-2? -Hydroxymethyl-2 -methyl-propylimino) - methyl] -phenol with 2,4-di-ert-butyl-6- [1-S-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol.

The desired enantiomer is thus obtained. [α] ⁰ _D : +185.9 (c 0.1, DMF).

Example 6 Preparation of {S) - (-) -tenatoprazole

1.2 L of NMP are then introduced into a 5 L flask and then 240 g of 5-methoxy-2- [[4-methoxy-3, 5-dimethyl] -2 -pyridyl) - methyl] thio] imidazo [4 , 5-b] pyridine. The mixture is left stirring at room temperature for 1 h 30 min. 18 ml of NMP, 2.9 g of (12?, 23) - 1 - [2-hydroxy-3,5, di-tert-butyl-benzylidene) -amino] - are successively introduced into a 50 ml flask indan-2-ol, then 1.9 g of vanadium acetylacetonate. The mixture is stirred at room temperature. After 1.5 hours of stirring, this solution is added to the reaction medium.

To this mixture, with stirring, 95 ml of 30% hydrogen peroxide are added for 20 h at room temperature. The reaction medium is precipitated by adding 500 ml of water.

The precipitate is recovered by filtration and then it is taken up in 5 L of chloroform. The organic phase is washed twice with water, then dried and concentrated under reduced pressure. 126 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 30% (yield 50%). A series of recrystallizations is carried out in a DMF / ethyl acetate mixture and the enantiomer is obtained with an enantiomeric excess greater than 99%. Example 7

Preparation of (S) - (-) -tenatoprazole 3.7 L of acetone are introduced into a 10 L flask and then 30 g of 5-methoxy-2 - [[4 -methoxy-3, 5-dimethyl] - 2 -pyridyl) - methyl] thio] imidazo [4, 5-b] pyridine. The mixture is left stirring at room temperature for 30 min.

30 ml of acetonitrile, 1.66 g of (12?, 23) -1- [2-hydroxy-3,5, di-tert-butyl-benzylidene) -amino] are successively introduced into a 100 ml flask -indan-2-ol, then 1.19 g of vanadium acetylacetonate. The mixture is stirred at room temperature. After 1.5 hours of stirring, this suspension is added to the reaction medium.

To this mixture, with stirring, 10 g of urea-H ₂ 0 ₂ dissolved in 7 ml of water and 50 ml of acetone are added over a period of 6 hours. Then allowed to stir for 12 hours at room temperature. A solution of sodium metabisulfite is added, then a 20% ammonia solution and the acetone is concentrated. Wash with 100 mL of chloroform. The aqueous phase is recovered and then neutralized with acetic acid. Extraction is carried out twice with 200 ml of chloroform. After separation of the aqueous phase, the organic phase is dried and concentrated under reduced pressure. 19 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 50% (yield 60%). A series of recrystallizations is carried out in a DMF / ethyl acetate mixture and the enantiomer is obtained with an enantiomeric excess greater than 99%.

Example 8

Preparation of {S) - (-) -tenatoprazole 4 L of acetone are introduced into a 10 L flask and then 30 g of 5-methoxy-2- [[4-methoxy-3, 5-dimethyl] -2- pyridyl) - methyl] thio] imidazo [4, 5-b] pyridine. The mixture is left stirring at room temperature for 30 min.

25 ml of acetonitrile, 1.66 g of (12 ?, 2S) - 1 - [2-hydroxy-3, 5-di- are successively introduced into a 100 ml flask tert-butyl-benzylidene) -amino] -indan-2-ol, then 1.19 g of vanadium acetylacetonate. The mixture is stirred at room temperature. After 30 min of stirring, this suspension is added to the reaction medium. To this mixture, with stirring, 30 g of sodium sulphate are added, then 10 g of urea-H ₂ 0 ₂ dissolved in 7 ml of water and 50 ml of acetone over a period of 6 hours. Then allowed to stir for 12 hours at room temperature. A solution of sodium metabisulfite is added, then a 20% ammonia solution and the acetone is concentrated. Wash with 100 mL of chloroform. The aqueous phase is recovered and then neutralized with acetic acid. Extraction is carried out twice with 200 ml of chloroform. After separation of the aqueous phase, the organic phase is dried and concentrated under reduced pressure. 20.1 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 65% (yield 64%). A series of recrystallizations is carried out in a DMF / ethyl acetate mixture and the enantiomer is obtained with an enantiomeric excess greater than 99%.

Claims

1. Method for the enantioselective preparation of sulfoxide derivatives or their base salts, characterized in that it consists in carrying out an enantioselective oxidation of a sulfide of general formula (I) below

A - CH ₂ - S - B (I) in which A is a variously substituted pyridyl ring and B a heterocyclic residue comprising a benzimidazole or imidazo-pyridyl ring, by means of an oxidizing agent in the presence of a catalyst based on tungsten or vanadium and a chiral ligand, followed where appropriate by base salification, to obtain the sulfur oxide A - CH ₂ - SO - B (la).

2. Method according to claim 1, characterized in that, in the general formula (I), A represents a pyridyl group or a pyridyl group carrying one or more substituents chosen from linear or branched alkyl groups of 1 to 6 carbon atoms , linear or branched alkoxy of 1 to 6 carbon atoms, methyl or ethyl substituted by one or more halogen, amino, alkylamino or dialkylamino atoms in which the alkyl part, linear or branched, contains 1 to 5 carbon atoms; B represents a heterocycle chosen from the benzimidazole or imidazo- [4, 5-b] - pyridyl groups, substituted where appropriate by one or more linear or branched alkyl groups of 1 to 6 carbon atoms, linear or branched alkoxy of 1 to 6 carbon atoms,

3. Method according to claim 2, characterized in that the groups A and B are substituted on one or more carbons by a methyl, ethyl, methoxy or trihalogenomethyl group.

4. Method according to claim 3, characterized in that A is a 2 -pyridyl group substituted by one or more methyl, ethyl, methoxy or trifluoromethyl groups.

5. Method according to any one of claims 3 and 4, characterized in that A is a 4-methoxy-3, 5-dimethyl-2-pyridyl group and B is a 5-methoxy-1H-benzimidazolyl group or 5-methoxy-imidazo- [4, 5-b] -pyridyl.

6. Method according to any one of the preceding claims, characterized in that the enantiomer obtained is salified by the action of basic mineral reagents comprising against alkaline or alkaline-earth ions.

7. Method according to claim 6, characterized in that the salt is a sodium, potassium, lithium, magnesium or calcium salt.

8. Method according to any one of claims 1 to 7, characterized in that the oxidant is a peroxide or a hydroperoxide.

9. Method according to claim 8, characterized in that the oxidizing agent is hydrogen peroxide, urea-H ₂ 0 ₂ (UHP) or 1 hydroperoxide of cumene or tert-butyl.

10. Method according to any one of claims 1 to 9, characterized in that the catalyst is an oxo-vanadium complex (V) or a tungsten derivative.

11. Method according to claim 10, characterized in that the complex or the derivative is prepared from tungsten trioxide, vanadium acetylacetonate or vanadium sulfate.

12. Method according to any one of claims 1 to 11, characterized in that the catalyst is based on vanadium and the ligand is tridentate.

13. Method according to any one of claims 1 to 12, characterized in that the ligand is represented by the following general formula (II): where R is a hydrogen atom or a linear or branched alkyl group of 1 to 6 carbon atoms or an aryl or heteroaryl group; Ri to R ₄ , identical or different, represent a linear or branched alkyl group of 1 to 6 carbon atoms which can optionally be interrupted by a heteroatom such as sulfur, nitrogen and oxygen and / or be substituted by an amino group; an aryl group; an arylalkyl group; an alkoxycarbonyl group; a heteroaryl group or a heterocycle; a heteroarylalkyl group or a heterocyclalkyl group, with the proviso that R _x is not identical to R ₂ and / or R ₃ is not identical to R ₄ , so that the ligand has one or two centers of asymmetry ; Ri and R ₂ can together represent a carbonyl function C = 0;

Ri and R ₃ , or R ₂ and R ₄ , can together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system with 9 or 10 carbon atoms, one of the rings of which may be aromatic; R ₄ and R can form, with the nitrogen atom, a 5 or 6-membered heterocycle;

R ₅ and R ₆ , identical or different, represent a linear or branched alkyl group of 1 to 6 carbon atoms or a carbon ring comprising 5 or 6 members, or form a heterocycle with the nitrogen atom to which they are attached, or R5 and R ₆ together represent with nitrogen a double bond -N = CHAr where Ar is an aryl group which can comprise from 1 to 3 substituents, preferably carrying a hydroxyl group.

14. The method of claim 13, characterized in that Ar is a 2 '-hydroxyphenyl group optionally substituted on the aryl group.

15. The method of claim 13 or 14, characterized in that Ri and R ₃ , or R ₂ and R ₄ , represent a hydrogen atom, while R ₂ and R ₄ , or Ri and R ₃ , respectively, are , independently of each other, linear or branched alkyl groups of 1 to 6 carbon atoms, an aryl group or together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system of 9 or 10 carbon atoms of which l 'one of the cycles can be aromatic.

16. Method according to any one of claims 13 to 15, characterized in that the aryl group is chosen from the phenyl group, the naphthyl group, the tetra group hydronaphthyl, the indanyl group and the binaphthyl group, this aryl group possibly being substituted by 1 to 3 substituents chosen independently of one another from a hydroxyl group, a linear or branched alkyl group comprising from 1 to 4 carbon atoms, a nitro group , a group (Cι-C ₄ ) alkoxy and a halogen atom.

17. Method according to any one of claims 13 to 16, characterized in that the ligand of formula (II) is alternately derived: - from an amino alcohol of formula (III)

in which Ri, R ₂ , R ₃ and R ₄ are as defined in any one of claims 13 to 16,

- an amino ether of formula (IV)

in which R, Ri, R ₂ , R ₃ and R ₄ are as defined in any one of Claims 13 to 16,

- an amino acid of formula (V)

in which R 'takes the definition of R ₃ or R ₄ according to any one of claims 13 to 16 or,

- an amino ester of formula (VI)

R NH ₂

OX ^ OR " ^m) in which R 'takes the definition of R ₃ or R ₄ according to any one of claims 13 to 16 and R''takes the definition of R according to any of claims 13 to 16.

18. Method according to claim 17, characterized in that the amino alcohol of formula (III) is chosen from L- OR D-valinol, 2? - tert-leucinol, S- tert-leucinol and

(15.22?) - (-) - or (12?, 2S) - (+) -1-amino-2-indanol and in that the amino acid of formula (V) is chosen from -valine or

D-valine, -phenylalanine or D-phenylalanine, L-methionine or D-methionine, -histidine or D-histidine, L-lysine or D-lysine.

19. Method according to any one of claims 13 to 18, characterized in that the ligand of formula (II) is obtained by reacting an amino alcohol, an amino ether, an amino acid or an amino ester respectively of formula (III), (IV), (V) and (VI) as defined in claims 17 or 18 with an aldehyde of salicylic acid, of formula (VII)

in which R ₇ represents 1 to 2 substituents chosen independently of one another from a hydroxyl group, a linear or branched alkyl group comprising from 1 to 4 carbon atoms, a nitro group, a (Cι_C ₄ ) alkoxy group and a d atom 'halogen.

20. Method according to any one of claims 13 to 19, characterized in that one uses a catalyst prepared from vanadium acetylacetonate and a ligand derived from an amino alcohol or an amino ether respectively of formula (III) or (IV) defined in claim 17 or 18.

21. Method according to claim 20, characterized in that the ligand of formula (II) is derived from an amino alcohol of formula (III) as defined in claim 17, for which

R ₅ and R ₆ together represent with nitrogen a double bond -N = CHAr where Ar is an aryl group comprising from 1 to 3 substituents and at least one hydroxyl group, Ar being preferably a phenyl group, Ri and R ₃ , or R ₂ and R ₄ , represent a hydrogen atom, while R ₂ and R ₄ , or Ri and R ₃ , respectively, are, independently of each other, linear or branched alkyl groups of 1 to 6 carbon atoms, preferably a tert-butyl group or together form a carbon ring of 5 or 6 carbon atoms or a bicyclic system with 9 or 10 carbon atoms of which one of the rings can be aromatic, preferably indanyl.

22. Method according to any one of claims 13 to 19, characterized in that a catalyst is prepared prepared from vanadium sulphate and a ligand derived from an amino acid or an amino ester respectively of formula ( V) or (VI) as defined in claim 17 or 18.

23. Method according to any one of claims 1 to 21, characterized in that the ligand is 2,4-di-tert-butyl-6- [l-2? -Hydroxymethyl-2-methyl-propylimino) -methyl ] - phenol, 2,4-di-tert-butyl-6- [1S-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol, (12 ?, 23) - 1 - [2-hydroxy-3 , 5-di-tert-butyl-benzylidene) -amino] -indan-2-ol or le (1S, 22?) -1- [2- hydroxy-3, 5-di- tert-butyl-benzylidene) -amino ] -indan-2-ol.

24. The method of claim 23, characterized in that the ligand is in solution in acetonitrile.

25. The method of claim 23 or 24, characterized in that one carries out an enantioselective oxidation of 5-methoxy-2- [[((4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] - imidazo [4, 5-b] pyridine to obtain the (-) -5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] suifinyl] imidazo [4, 5- b] - pyridine using a vanadium-based catalyst combined with a ligand consisting of 2,4-di-tert-butyl-6- [1-2-? -hydroxy-methyl-2-methyl-propylimino) -methyl] -phenol or (12 ?, 2S) - 1 - [2-hydroxy-3, 5-di-tert-butyl-benzylidene) -amino] -indan-2-ol in solution in acetonitrile, while sulfide is in solution in dichloromethane, or respectively in acetone or N-methylpyrrolidinone.

26. Method according to any one of claims 10 or 11, characterized in that the catalyst is a derivative of tungsten and the ligand is 2, 5-diphenyl-4, 6-pyridinyl hydroquinine diether (DHQ) ₂ -PYR or 2, 5-diphenyl-4, 6-pyridinyl hydroquinidine diether (DHQD) ₂ -PYR .

27. The method of claim 26, characterized in that an enantioselective oxidation of the

5-methoxy-2- [[((4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] - imidazo [4, 5-b] pyridine by hydrogen peroxide in the presence of tungsten trioxide and (DHQD) ₂ -PYR to obtain (-) - 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] suifiyl] imidazo [4, 5-b] pyridine.

28. Method according to any one of the preceding claims, characterized in that the oxidation reaction is carried out in a solvent, in a neutral or weakly basic medium.

29. Method according to claim 28, characterized in that the solvent is a mixture of solvents consisting of a specific solvent for sulfide and a specific solvent for the ligand chosen from the group consisting of methanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetone, chloroform, dimethylformamide and N-methylpyrrolidinone, alone or as a mixture, and the base is a tertiary amine chosen from pyridine, di-isopropylethylamine and triethylamine.